On the path to a new-generation malaria vaccine

New approach using genetically modified parasite ‘primes the immune system’ in first human trial

January 4, 2017•By Mary Engel / Fred Hutch News Service

Volunteers endured 150 to 200 mosquito bites in one 10-minute session to test whether the new approach produced the expected immune response without causing disease. For now, the genetically modified parasites can only be produced in the salivary glands of mosquitoes. Photo by iStock

Researchers may be one step closer to a truly effective malaria vaccine, a new study suggests. A genetically modified malaria parasite worked as designed in its first human clinical trial, causing neither malaria nor serious safety problems in the 10 people who volunteered to be infected. It also stimulated an immune response that holds out promise of a more protective vaccine than the single candidate now in pilot studies

“Our approach permanently and uniformly cripples the very complex malaria parasite so that it cannot cause disease and, instead, effectively primes the immune system,” CIDR’s Dr. Stefan Kappe, one of the paper’s main authors, said in a statement.

Malaria is caused by the Plasmodium parasite and spreads to humans through the bite of an infectious mosquito. With 5,000 genes and a life cycle that involves multiple stages in humans and mosquitos, Plasmodium is far more complex than disease-causing viruses, complicating efforts to develop a vaccine against it.

One vaccine strategy, called attenuation, “teaches” the immune system what to guard against by presenting it with a live but weakened, or attenuated, version of the infecting agent. Viruses are often attenuated by growing generations of them in cultures until they lose some of their fight.

Kappe, a CIDR professor and an affiliate professor at the University of Washington’s Department of Global Health, developed a way to weaken the malaria parasite by knocking out three genes that the organism needs to replicate in the human liver and re-emerge in the bloodstream to cause illness. Called GAP for genetically attenuated parasite, it marks the first time genetic engineering has been used to combat any parasitic disease.

Fred Hutch’s Dr. Jim Kublin, the paper’s first author, led the clinical trial of GAP in humans. At this time, GAPs can only be produced in the salivary glands of mosquitos. So in the trial, each of the 10 volunteers placed their arms over a net-covered cup of mosquitoes and endured 150 to 200 bites in one 10-minute session.

Kublin was pleased with the trial results — and impressed by the volunteers.

“It’s exciting to see the triple [gene] knockout appear fully attenuated and generally safe and well-tolerated,” he said in an interview, while noting that developing a better — and more comfortable — delivery method was a high priority.

As for the volunteers, they were “fantastic,” he said, adding, “All of them said they were willing to come back for more, which is so cool.”

Progress against a deadly disease

The World Health Organization estimates that 438,000 people died of malaria in 2015, most of them children under age 5, and more than 200 million were sickened. Half the world’s population live in areas where the disease is transmitted.

About 15 years ago, world leaders called for a renewed effort to fight the deadly disease. Since then, widespread distribution of insecticide-treated bed nets and a new combination of medicines have reduced deaths by more than 50 percent, down from 1 million. But because of the threat that the parasite could develop resistance to medications or insecticides, global health experts consider a vaccine to be a vital tool.

The most advanced malaria vaccine candidate to date, called RTS,S, uses a fragment of the parasite — a major protein on its surface — to elicit an immune response. It is the only malaria vaccine candidate to have made it as far as a Phase 3 trial.

Results of that trial, published in 2015, showed about one-third fewer episodes of clinical and severe malaria in young children who received three vaccine doses and a booster, with protection waning over time. Additional analysis by Fred Hutch researchers and others found that the experimental vaccine works better against one strain of the disease-causing parasite than others, explaining its limited protection and providing insights into how to best deploy it. Although no countries have yet licensed RTS,S, the WHO has announced funding for pilot implementation in three to five sub-Saharan countries, beginning in 2018.

The Phase 1 study of GAP focused on safety and immune responses; it did not directly test whether the immune responses that were elicited actually protected against malaria infection. Now that GAP has been shown to be safe, the next step will be a second clinical trial that delivers GAPs to volunteers and then exposes them to a strain of malaria that is easily diagnosed and responds to conventional treatment. Called a controlled human challenge trial, it is planned for later this year.

Dr. Jim KublinRobert Hood / Fred Hutch

“Because of overcoming the hurdle of attenuation and showing that [GAP] is generally safe, we can proceed to a full efficacy evaluation by controlled human challenge trial,” said Kublin. “There are few places in the world that can do that kind of trial.”

A ‘heroic effort’

CIDR’s Human Challenge Center is one of only four places in the world and the only non-military center in the United States with an “insectary” for breeding malaria-carrying mosquitos. It is part of the Seattle Malaria Clinical Trials Center, run by CIDR and Fred Hutch and based at the Hutch. The Hutch base also conducts malaria human challenge trials that deliver malaria sporozoites — the infectious form of the parasite ordinarily introduced into human blood by a mosquito’s bite — via direct venous inoculation. Down the road, this approach, developed by the U.S. biotechnology company Sanaria, could offer a more practical and more scalable delivery method for GAPs, Kublin said.

Much, if not all, of the discomfort endured by volunteers in the Phase 1 trial came from getting 200 mosquito bites all at once, according to Kublin. Reactions included itching, redness, swelling and fatigue. One of the volunteers didn’t sleep the first night because the itching was so intense.

Volunteers had been thoroughly screened and informed that such reactions were likely. Their symptoms were treated with topical ointments and steroids.

“We knew that 200 mosquito bites on the forearm would elicit [those symptoms], and we wanted to make sure people understood that and were nonetheless willing to participate,” Kublin said.

After being carefully monitored for reactions for the first seven days, the volunteers were housed at a hotel for 10 additional days so that researchers could keep a close watch, using blood smears, for breakthrough malaria infections. None occurred.

Volunteers received about $2,000 to compensate for their time, but Kublin believed that the main motive for going through what they did was altruism.

“It was a heroic kind of effort, that they were willing to do this,” he said. “That the volunteers, despite the discomfort, said that they would be willing to come back and do it again was testament to their commitment.”

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Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.

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